tbuckley/cabot-search huggingface dataset:
GelMA and Biomimetic Culture Allow the Engineering of Mineralized, Adipose, and Tumor Tissue Human Microenvironments for the Study of Advanced Prostate Cancer In Vitro and In Vivo
Authors: Agathe Bessot, Jennifer Gunter, David Waugh, Judith A. Clements, Dietmar W. Hutmacher, Jacqui McGovern, Nathalie Bock
Journal: Advanced Healthcare Materials (2023)

Increasing evidence shows bone marrow (BM)-adipocytes as a potentially important contributor in prostate cancer (PCa) bone metastases. However, a lack of relevant models has prevented the full understanding of the effects of human BM-adipocytes in this microenvironment. It is hypothesized that the combination of tunable gelatin methacrylamide (GelMA)-based hydrogels with the biomimetic culture of human cells would offer a versatile 3D platform to engineer human bone tumor microenvironments containing BM-adipocytes. Human osteoprogenitors, adipocytes, and PCa cells are individually cultured in vitro in GelMA hydrogels, leading to mineralized, adipose, and PCa tumor 3D microtissues, respectively. Osteoblast mineralization and tumor spheroid formation are tailored by hydrogel stiffness with lower stiffnesses correlating with increased mineralization and tumor spheroid size. Upon coculture with tumor cells, BM-adipocytes undergo morphological changes and delipidation, suggesting reciprocal interactions between the cell types. When brought in vivo, the mineralized and adipose microtissues successfully form a humanized fatty bone microenvironment, presenting, for the first time, with human adipocytes. Using this model, an increase in tumor burden is observed when human adipocytes are present, suggesting that adipocytes support early bone tumor growth. The advanced platform presented here combines natural aspects of the microenvironment with tunable properties useful for bone tumor research.
The application of nanoparticles in immunotherapy for hepatocellular carcinoma
Authors: Xinyao Hu, Hua Zhu, Xiaoqin He, Jiayu Chen, Lin Xiong, Yang Shen, Jiayi Li, Yangtao Xu, Wenliang Chen, Xin Liu, Dedong Cao, Ximing Xu
Journal: Journal of Controlled Release (2023)
Adhesive hydrogels in osteoarthritis: from design to application
Authors: Wang-Lin Duan, Li-Ning Zhang, Raghvendra Bohara, Sergio Martin-Saldaña, Fei Yang, Yi-Yang Zhao, Yong Xie, Ya-Zhong Bu, Abhay Pandit
Journal: Military Medical Research (2023)

Osteoarthritis (OA) is the most common type of degenerative joint disease which affects 7% of the global population and more than 500 million people worldwide. One research frontier is the development of hydrogels for OA treatment, which operate either as functional scaffolds of tissue engineering or as delivery vehicles of functional additives. Both approaches address the big challenge: establishing stable integration of such delivery systems or implants. Adhesive hydrogels provide possible solutions to this challenge. However, few studies have described the current advances in using adhesive hydrogel for OA treatment. This review summarizes the commonly used hydrogels with their adhesion mechanisms and components. Additionally, recognizing that OA is a complex disease involving different biological mechanisms, the bioactive therapeutic strategies are also presented. By presenting the adhesive hydrogels in an interdisciplinary way, including both the fields of chemistry and biology, this review will attempt to provide a comprehensive insight for designing novel bioadhesive systems for OA therapy.
Phenotypic correlations of CALR mutation variant allele frequency in patients with myelofibrosis
Authors: Paola Guglielmelli, Chiara Maccari, Benedetta Sordi, Manjola Balliu, Alessandro Atanasio, Carmela Mannarelli, Giulio Capecchi, Ilaria Sestini, Giacomo Coltro, Giuseppe Gaetano Loscocco, Giada Rotunno, Eva Angori, Filippo C. Borri, Ayalew Tefferi, Alessandro M. Vannucchi
Journal: Blood Cancer Journal (2023)

Dear Editor
Pharmacokinetics and Pharmacodynamics of a Novel U500 Insulin Aspart Formulation: A Randomized, Double-Blind, Crossover Study in People With Type 1 Diabetes
Authors: Eva Svehlikova, Nicole L. Ashcroft, Christina Gatschelhofer, David Gerring, Vera Höller, Jan Jezek, Bettina Lackner, Fiona Lawrence, Vijay Pillai, Maria Ratzer, Martina Urschitz, Michael Wolf, Thomas R. Pieber
Journal: Diabetes Care (2023)

OBJECTIVE To evaluate the pharmacokinetics, pharmacodynamics, and safety of a novel U500 insulin aspart formulation (AT278 U500) compared with insulin aspart (IAsp U100). RESEARCH DESIGN AND METHODS This single-center, randomized, double-blind study was conducted in 38 men with type 1 diabetes (body weight ≤100 kg and total insulin dose &amp;lt;1.2 units/kg/day). Participants received a single dose of either AT278 U500 or IAsp U100 (0.3 units/kg s.c.) in a crossover design, followed by an 8-h euglycemic clamp in the absence of basal insulin. RESULTS With AT278 U500, onset of appearance in serum was 6 min earlier (P &amp;lt; 0.0001) and reached 50% of maximum concentration 23 min faster (P &amp;lt; 0.0001). Insulin exposure with AT278 U500 was 4.0-fold higher within the first 30 min (95% CI 3.29, 4.90), 1.5-fold higher within the first 60 min (95% CI 1.35, 1.76), and statistically superior up to 90 min postdose (P &amp;lt; 0.05). With AT278 U500, onset of action was 10 min earlier (P &amp;lt; 0.0001) and reached 50% of maximum glucose infusion rate 20 min faster (P &amp;lt; 0.0001). The glucose-lowering effect with AT278 U500 was 8.9-fold higher within the first 30 min (95% CI 5.96, 17.46), 2.4-fold higher within the first 60 min (95% CI 1.92, 3.22), and statistically superior up to 2 h postdose (P &amp;lt; 0.0001). Overall insulin exposure and glucose-lowering effect were comparable. No significant safety findings were observed. CONCLUSIONS AT278 U500 offers rapid-acting characteristics in a reduced dose volume, with accelerated absorption and onset of action compared with IAsp U100 in the studied population.
Utility of combining PIVKA-II and AFP in the surveillance and monitoring of hepatocellular carcinoma in the Asia-Pacific region
Authors: Do Young Kim, Bao Nguyen Toan, Chee-Kiat Tan, Irsan Hasan, Lyana Setiawan, Ming-Lung Yu, Namiki Izumi, Nguyen Nguyen Huyen, Pierce Kah-Hoe Chow, Rosmawati Mohamed, Stephen Lam Chan, Tawesak Tanwandee, Teng-Yu Lee, Thi Thanh Nguyen Hai, Tian Yang, Woo-Chang Lee, Henry Lik Yuen Chan
Journal: Clinical and Molecular Hepatology (2023)

Even though the combined use of ultrasound (US) and alpha-fetoprotein (AFP) is recommended for the surveillance of hepatocellular carcinoma (HCC), the utilization of AFP has its challenges, including accuracy dependent on its cut-off levels, degree of liver necroinflammation, and etiology of liver disease. Though various studies have demonstrated the utility of protein induced by vitamin K absence II (PIVKA-II) in surveillance, treatment monitoring, and predicting recurrence, it is still not recommended as a routine biomarker test. A panel of 17 experts from Asia-Pacific, gathered to discuss and reach a consensus on the clinical usefulness and value of PIVKA-II for the surveillance and treatment monitoring of HCC, based on six predetermined statements. The experts agreed that PIVKA-II was valuable in the detection of HCC in AFP-negative patients, and could potentially benefit detection of early HCC in combination with AFP. PIVKA-II is clinically useful for monitoring curative and intra-arterial locoregional treatments, outcomes, and recurrence, and could potentially predict microvascular invasion risk and facilitate patient selection for liver transplant. However, combining PIVKA-II with US and AFP for HCC surveillance, including small HCC, still requires more evidence, whilst its role in detecting AFP-negative HCC will potentially increase as more patients are treated for hepatitis-related HCC. PIVKA-II in combination with AFP and US has a clinical role in the Asia-Pacific region for surveillance. However, implementation of PIVKA-II in the region will have some challenges, such as requiring standardization of cut-off values, its cost-effectiveness and improving awareness among healthcare providers.
Clinical practice guidelines and real-life practice in hepatocellular carcinoma: A Taiwan perspective
Authors: Tung-Hung Su, Chih-Horng Wu, Tsung-Hao Liu, Cheng-Maw Ho, Chun-Jen Liu
Journal: Clinical and Molecular Hepatology (2023)

Hepatocellular carcinoma (HCC) is the fourth most common cancer and the second leading cause of cancer-related death in Taiwan. The Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan developed and updated the guidelines for HCC management in 2020. In clinical practice, we follow these guidelines and the reimbursement policy of the government. In Taiwan, abdominal ultrasonography, alpha-fetoprotein, and protein induced by vitamin K absence or antagonist-II (PIVKA-II) tests are performed for HCC surveillance every 6 months or every 3 months for high-risk patients. Dynamic computed tomography, magnetic resonance imaging, and contrast-enhanced ultrasound have been recommended for HCC surveillance in extremely high-risk patients or those with poor ultrasonographic visualization results. HCC is usually diagnosed through dynamic imaging, and pathological diagnosis is recommended. Staging of HCC is based on a modified version of the Barcelona Clinic Liver Cancer (BCLC) system, and the HCC management guidelines in Taiwan actively promote curative treatments including surgery and locoregional therapy for BCLC stage B or C patients. Transarterial chemoembolization (TACE), drug-eluting bead TACE, transarterial radioembolization, and hepatic artery infusion chemotherapy may be administered for patients with BCLC stage B or C HCC. Sorafenib and lenvatinib are reimbursed as systemic therapies, and regorafenib and ramucirumab may be reimbursed in cases of sorafenib failure. First-line atezolizumab with bevacizumab is not yet reimbursed but may be administered in clinical practice. Systemic therapy and external beam radiation therapy may be used in specific patients. Early switching to systemic therapy in TACE-refractory patients is a recent paradigm shift in HCC management.
Long-term reversal of chronic pain behavior in rodents through elevation of spinal agmatine
Authors: Cristina D. Peterson, Jonathan J. Waataja, Kelley F. Kitto, Samuel J. Erb, Harsha Verma, Daniel J. Schuster, Caroline C. Churchill, Maureen S. Riedl, Lalitha R. Belur, Daniel A. Wolf, R. Scott McIvor, Lucy Vulchanova, George L. Wilcox, Carolyn A. Fairbanks
Journal: Molecular Therapy (2023)

Chronic pain remains a significant burden worldwide, and treatments are often limited by safety or efficacy. The decarboxylated form of L-arginine, agmatine, antagonizes N-methyl-d-aspartate receptors, inhibits nitric oxide synthase, and reverses behavioral neuroplasticity. We hypothesized that expressing the proposed synthetic enzyme for agmatine in the sensory pathway could reduce chronic pain without motor deficits. Intrathecal delivery of an adeno-associated viral (AAV) vector carrying the gene for arginine decarboxylase (ADC) prevented the development of chronic neuropathic pain as induced by spared nerve injury in mice and rats and persistently reversed established hypersensitivity 266 days post-injury. Spinal long-term potentiation was inhibited by both exogenous agmatine and AAV-human ADC (hADC) vector pre-treatment but was enhanced in rats treated with anti-agmatine immunoneutralizing antibodies. These data suggest that endogenous agmatine modulates the neuroplasticity associated with chronic pain. Development of approaches to access this inhibitory control of neuroplasticity associated with chronic pain may yield important non-opioid pain-relieving options. Chronic pain remains a significant burden worldwide, and treatments are often limited by safety or efficacy. The decarboxylated form of L-arginine, agmatine, antagonizes N-methyl-d-aspartate receptors, inhibits nitric oxide synthase, and reverses behavioral neuroplasticity. We hypothesized that expressing the proposed synthetic enzyme for agmatine in the sensory pathway could reduce chronic pain without motor deficits. Intrathecal delivery of an adeno-associated viral (AAV) vector carrying the gene for arginine decarboxylase (ADC) prevented the development of chronic neuropathic pain as induced by spared nerve injury in mice and rats and persistently reversed established hypersensitivity 266 days post-injury. Spinal long-term potentiation was inhibited by both exogenous agmatine and AAV-human ADC (hADC) vector pre-treatment but was enhanced in rats treated with anti-agmatine immunoneutralizing antibodies. These data suggest that endogenous agmatine modulates the neuroplasticity associated with chronic pain. Development of approaches to access this inhibitory control of neuroplasticity associated with chronic pain may yield important non-opioid pain-relieving options.
CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances
Authors: Karama Makni Maalej, Maysaloun Merhi, Varghese P. Inchakalody, Sarra Mestiri, Majid Alam, Cristina Maccalli, Honar Cherif, Shahab Uddin, Martin Steinhoff, Francesco M. Marincola, Said Dermime
Journal: Molecular Cancer (2023)

In the last decade, Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach to fight cancers. This approach consists of genetically engineered immune cells expressing a surface receptor, called CAR, that specifically targets antigens expressed on the surface of tumor cells. In hematological malignancies like leukemias, myeloma, and non-Hodgkin B-cell lymphomas, adoptive CAR-T cell therapy has shown efficacy in treating chemotherapy refractory patients. However, the value of this therapy remains inconclusive in the context of solid tumors and is restrained by several obstacles including limited tumor trafficking and infiltration, the presence of an immunosuppressive tumor microenvironment, as well as adverse events associated with such therapy. Recently, CAR-Natural Killer (CAR-NK) and CAR-macrophages (CAR-M) were introduced as a complement/alternative to CAR-T cell therapy for solid tumors. CAR-NK cells could be a favorable substitute for CAR-T cells since they do not require HLA compatibility and have limited toxicity. Additionally, CAR-NK cells might be generated in large scale from several sources which would suggest them as promising off-the-shelf product. CAR-M immunotherapy with its capabilities of phagocytosis, tumor-antigen presentation, and broad tumor infiltration, is currently being investigated. Here, we discuss the emerging role of CAR-T, CAR-NK, and CAR-M cells in solid tumors. We also highlight the advantages and drawbacks of CAR-NK and CAR-M cells compared to CAR-T cells. Finally, we suggest prospective solutions such as potential combination therapies to enhance the efficacy of CAR-cells immunotherapy.
Design, synthesis, and applications of ring‐functionalized histidines in peptide‐based medicinal chemistry and drug discovery
Authors: Komal Sharma, Krishna K. Sharma, Amit Mahindra, Naina Sehra, Nitin Bagra, Shams Aaghaz, Rajesh Parmar, Gajanan K. Rathod, Rahul Jain
Journal: Medicinal Research Reviews (2023)

Abstract Modified and synthetic α‐amino acids are known to show diverse applications. Histidine, which possesses numerous applications when subjected to synthetic modifications, is one such amino acid. The utility of modified histidines varies widely from remarkable biological activities to catalysis, and from nanotechnology to polymer chemistry. This renders histidine residue an important place in scientific research. Histidine is a well‐studied scaffold and constitutes the active site of various enzymes catalyzing important reactions in the biological systems. A rational modification in histidine structure with a distinctly developed protocol extensively changes its physical and chemical properties. The utilization of modified histidines in search of potent, target selective and proteostable scaffolds is vital in the development of bioactive peptides with enhanced drug‐likeliness. This review is a compilation and analysis of reported side‐chain ring modifications at histidine followed by applications of ring‐modified histidines in the synthesis of various categories of bioactive peptides and peptidomimetics.
Immunomodulation in Septic Shock
Authors: JOSEF BRIEGEL, MARGARETHE JOCHUM, CORNELIA GIPPNER-STEPPERT, MANFRED THIEL
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Cortisol is known to be an immunomodulatory hormone that exerts suppressive and permissive effects on the immune response. Little is known regarding the evolution of the cytokine response in human septic shock in the presence of hypercortisolemia induced by infusion of stress doses of hydrocortisone. Twenty-four consecutive patients with high-out-put circulatory failure (cardiac index, >4 liters/min per m2) who met the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee criteria for septic shock were enrolled in a prospective, double-blind study. The severity of illness at the time of enrollment was graded using the Acute Physiology and Chronic Health Evaluation II system, and the evolution of sepsis-induced organ dysfunction syndrome was assessed using Sepsis-Related Organ Failure Assessment scores. After randomization, hyper-cortisolemia was induced in 12 patients by infusion of 100 mg of hydrocortisone, followed by continuous infusion of 0.18 mg/kg per h. Levels of the circulating cytokines tumor necrosis factor α (TNF), interleukin 6 (IL-6), IL-8, and IL-10 were serially measured at prospectively defined time points during the first 5 d after randomization. The infusion of hydrocortisone was associated with significant reductions in serum IL-6 and IL-8 levels and with earlier resolution of the sepsis-induced organ dysfunction syndrome. IL-6 levels started to differ between the groups on day 5. The TNF and IL-10 responses were not altered by hydrocortisone infusion. Hydrocortisone infusion in septic shock differentially regulated the cytokine responses. IL-6 and IL-8 levels decreased significantly and IL-6 levels differed between the groups, whereas TNF and IL-10 levels were not affected by hydrocortisone. Stress doses of hydrocortisone may be a valuable immunomodulatory therapy for septic shock.
Balance of DNA methylation and demethylation in cancer development
Authors: Chun-Xiao Song, Chuan He
Journal: Genome biology (2012)

Genome-wide 5-hydroxymethylome analysis of a rodent hepatocarcinogen model reveals that 5-hydroxymethylcytosine-dependent active DNA demethylation may be functionally important in the early stages of carcinogenesis. See research article http://genomebiology.com/2012/13/10/R93
Interpretation of Plasma on Studies With
Authors: Joseph R. Bloomer
Journal: JAMA (1971)

The plasma unconjugated bilirubin concentration (Br) is related to the bilirubin production rate (BRP) and hepatic bilirubin clearance (C<sub>Br</sub>) in the following manner: Br = BRP ÷ C<sub>Br</sub>. The distribution for Br in the normal population was calculated from this relationship, using normal values of BRP and C<sub>Br</sub>measured with labeled bilirubin. The results indicate that any individual with a Br exceeding 1.0 mg/100 ml (99% level) should be suspected of having abnormal hepatic function or bilirubin overproduction or both. A Br greater than 3.5 mg/100 ml usually indicates abnormal hepatic function, regardless of the BRP. A change in Br means that either bilirubin production or hepatic function has been altered, even if Br remains within the normal range.
Lateral Medullary Syndrome in a Child
Authors: Robert A. Klein
Journal: JAMA (1976)

THE MAJORITY of cerebrovascular accidents in children involve the carotid circulation.<sup>1</sup>The few that have occurred in the vertebrobasilar circulation usually involve occlusion within the basilar artery.<sup>2</sup> We report the sudden onset of a typical lateral medullary (Wallenberg) syndrome in a boy. Vertebral artery occlusion was shown roentgenographically. Previous reports of a Wallenberg syndrome in children have been rare and atypical.<sup>3,4</sup> <h3>Report of a Case</h3> An 8-year-old Navajo boy had a minor fall on the right side of his face, with no apparent injury and no loss of consciousness. On the following day, he complained of vomiting, dizziness, staggering, weakness on the left side, difficulty in swallowing, and severe headache. Positive findings on neurologic examination included lethargy, horizontal nystagmus most marked on left gaze, hypalgesia on the left side of the face, absent left corneal reflex, left facial paresis including the frontalis muscle, absent gag reflex bilaterally,
Medical Students' Attitudes Toward Providing Care for the Underserved
Authors: Sonia J. S. Crandall
Journal: JAMA (1993)

<h3>Objective.</h3> —To investigate the association between attitudes toward caring for the medically indigent and years of medical training. <h3>Design.</h3> —Questionnaire comparing attitudes of first-year medical students (MS-Is) and fourth-year medical students (MS-IVs). <h3>Setting.</h3> —Southwest medical school. <h3>Participants.</h3> —A total of 83 (67%) male and 41 (33%) female MS-I and 65 (73%) male and 24 (27%) female MS-IV volunteers. <h3>Main Outcome Measure.</h3> —Self-report, attitudinal scale developed for this study that provided a measure of overall attitudes, perceived societal expectations, physician/student responsibility, personal efficacy, and provision of basic services and expensive procedures. <h3>Results.</h3> —Overall attitudes were significantly less favorable for MS-IVs (95% confidence interval [CI], 99.6 to 106.2) than MS-Is (95% CI, 109.5 to 114.3,<i>P</i>&lt;.0001). Except for basic services (<i>P</i>=.46), MS-IVs had worse attitudes on all attitudes subscales. Male MS-IVs reported significantly less favorable attitudes than male MS-Is in the areas of general attitudes (<i>P</i>=.03) and physician/student responsibility (<i>P</i>=.01). Female medical students showed no significant differences across classes (<i>P</i>&gt;.05). Except for physician/student responsibility, female medical students' attitudes were more favorable than those of males, regardless of class. <h3>Conclusions.</h3> —The MS-IVs are less favorably inclined toward caring for the medically indigent than MS-Is, though these differences are apparent only for males. Further research is needed to explore why females appear to be more resistant to attitude changes, and what educational interventions are necessary to better train physicians to respond to national health care issues. (<i>JAMA</i>. 1993;269:2519-2523)
Links between COVID-19 and Parkinson’s disease/Alzheimer’s disease: reciprocal impacts, medical care strategies and underlying mechanisms
Authors: Pei Huang, Lin-Yuan Zhang, Yu-Yan Tan, Sheng-Di Chen
Journal: Translational Neurodegeneration (2023)

Abstract The impact of coronavirus disease 2019 (COVID-19) pandemic on patients with neurodegenerative diseases and the specific neurological manifestations of COVID-19 have aroused great interest. However, there are still many issues of concern to be clarified. Therefore, we review the current literature on the complex relationship between COVID-19 and neurodegenerative diseases with an emphasis on Parkinson’s disease (PD) and Alzheimer’s disease (AD). We summarize the impact of COVID-19 infection on symptom severity, disease progression, and mortality rate of PD and AD, and discuss whether COVID-19 infection could trigger PD and AD. In addition, the susceptibility to and the prognosis of COVID-19 in PD patients and AD patients are also included. In order to achieve better management of PD and AD patients, modifications of care strategies, specific drug therapies, and vaccines during the pandemic are also listed. At last, mechanisms underlying the link of COVID-19 with PD and AD are reviewed.